Electronic Structure and Reactions of Fe-oxo Enzymes

描述（由申请人提供）：铁氧和铁过氧酶活性位点的铁配合物的电子结构计算现在对理解这些系统的物理性质和反应化学做出了重要贡献。我们使用高质量的量子力学密度泛函理论（DFT）方法来描述和分析活性位点的性质，并将其与基于静电的更远距离蛋白质和溶剂环境的表示联系起来。我们的长期目标是发展对化学键，反应能量学和途径的详细了解，与实验结构，光谱和动力学研究密切联系。(1)这些DFT方法将用于计算铁氧和铁过氧酶的关键中间体的精确几何形状、能量和质子化状态。具体的酶感兴趣的是一类核糖核苷酸还原酶（RNRs），甲烷单加氧酶（MMOs），甲苯单加氧酶（Tolos）和Rieske加氧酶。(2)将与一些基于x射线、光学和电子/核的光谱学进行详细的联系。(3)对这些酶的反应途径进行评价，并与实验动力学进行比较。(4)对新的理论/计算方法进行检验，并与实验进行比较，进一步发展现代化学理论的力量和分析能力。rna催化核糖核苷酸转化为脱氧核糖核苷酸，这是DNA合成的第一个必要步骤，通常是速率限制步骤。因此，RNR是抗癌、抗病毒和抗菌治疗的药物靶点。MMOs、Tolos和Rieske加氧酶在有机污染物的解毒方面具有巨大的潜力，并且有望作为寻找环境无毒合成有价值化学品方法的指南。更好地了解这些酶的机制将有助于实现这些目标的实验工作。

DESCRIPTION (provided by applicant): Electronic structure calculations for the iron complexes at the active sites of iron-oxo and iron-peroxo based enzymes are now making an important contribution to understanding the physical properties and reaction chemistry of these systems. We use high-quality quantum mechanical density functional theory (DFT) methods to describe and analyze active site properties, and link this to an electrostatics-based representation of the longer range protein and solvent environment. Our long term goal to develop a detailed understanding of chemical bonding, reaction energetics and pathways, making a close connection with experimental structural, spectroscopic, and kinetics studies. (1) These DFT methods will be used to calculate accurate geometries, energies, and protonation states for critical intermediates of iron-oxo and iron-peroxo enzymes. The specific enzymes of interest are Class I ribonucleotide reductases (RNRs) methane monooxygenases (MMOs), toluene monoxygenases (Tolos) and Rieske oxygenases. (2) Detailed connections will be made to a number of X-ray, optical and electron/nuclear based spectroscopies. (3) Reaction pathways for these enzymes will be evaluated and compared with experimental kinetics. (4) New theoretical/computational methods will be tested and compared with experiment to further develop the power and analysis capabilities of modem chemical theory. RNRs catalyze the transformation of ribonucleotides to deoxyribonucleotides, the first required and often rate limiting step in DNA synthesis. Consequently, RNR is a drug target in anticancer, antiviral, and antibacterial therapies. MMOs, Tolos, and Rieske oxygenases have great potential for the detoxification of organic pollutants, and are promising as guides to finding environmentally nontoxic methods for the synthesis of valuable chemicals. A better understanding of these enzyme mechanisms should aid experimental work toward these goals.